Second only to the erythropoietic system in its traffic of iron, the liver is an organ where this essential metal is stored, utilized for the synthesis of iron enzymes indispensable to life, and recycled from the hemoglobin of senscent erythrocytes. Perhaps because of the continuous and bidirectional flux of iron across its cells, the liver is particularly vulnerable to the noxious effects of iron overload. Thus, almost all aspects of iron metabolism may be studied in this complex organ. Our approach is to examine iron metabolism in isolated liver cells, both hepatocytes and Kupffer cells, in order to gain deeper understanding of iron processing at cellular and molecular levels. Of particular interest is the interaction of transferrin with liver cells, with the protein acting either as iron donor to iron acceptor as the cells carry out their physiological functions in iron metabolism. We seek to study factors modulating the uptake and release of iron by hepatocytes, the relative importance of specific receptor-mediated and non-specific fluid-phase pathways in the uptake of iron from transferrin by hepatocytes, events and mechanisms in the elimination of iron acquired by Kupffer cells engated in erythrophagocytosis, and the cytotoxicity of iron when the burden of iron taken by erythrophagocytosing Kupffer cells exceeds the capacity of the cells to purge themselves of this vital but toxic element. Taken together, these studies may find application in the management of disorders of iron metabolism - among the most common and often the most disabling of humankind's ills.